Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity

Cancer Immunol Immunother. 2021 May;70(5):1165-1175. doi: 10.1007/s00262-020-02740-3. Epub 2020 Oct 26.


The solid tumor microenvironment is replete with factors that present a stress to infiltrating immune cells. Endoplasmic reticulum (ER) stress sensor PKR-like ER kinase (PERK) is primed to sense and respond to the burden of misfolded proteins in the ER lumen induced by cell stressors. PERK has documented roles as a master regulator of acute and chronic responses to cell stress as well as in the regulation of cell metabolism. Here, we provide an overview of the roles of PERK based on what is known and remains to be tested in immune cells in tumors and impacts on tumor control. PERK is one of several ER kinases able to preferentially induce activating transcription factor 4 (ATF4) as a response to cell stress. ATF4 orchestrates the oxidative stress response and governs amino acid metabolism. We discuss the tested role of ATF4 in tumor immunity and provide insight on the dueling protective and deleterious roles that ATF4 may play in the stress of solid tumors.

Keywords: ATF4; Cancer immunotherapy; ER stress; Metabolism; PERK; T cell; Translation.

Publication types

  • Review

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Endoplasmic Reticulum Stress / immunology*
  • Humans
  • Immunity
  • Immunotherapy / methods*
  • Neoplasms / immunology*
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment
  • eIF-2 Kinase / metabolism


  • Activating Transcription Factor 4
  • PERK kinase
  • eIF-2 Kinase